CA1190927A - Amidobenzamides, their salts, process for their preparation and pharmaceutical compositions containing them - Google Patents
Amidobenzamides, their salts, process for their preparation and pharmaceutical compositions containing themInfo
- Publication number
- CA1190927A CA1190927A CA000406813A CA406813A CA1190927A CA 1190927 A CA1190927 A CA 1190927A CA 000406813 A CA000406813 A CA 000406813A CA 406813 A CA406813 A CA 406813A CA 1190927 A CA1190927 A CA 1190927A
- Authority
- CA
- Canada
- Prior art keywords
- ylmethylthio
- pharmaceutically acceptable
- acid addition
- acceptable acid
- addition salt
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
- C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
- C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
- C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
Abstract
ABSTRACT OF THE DISCLOSURE
Amidobenzamides having histamine H2 receptors antagonising ac-tion, of formula wherein A is CO or SO2 and B is alkyl, phenyl, pyridyl, pyri-dyl 1-oxyde, pyrazinyl or thienyl; their salts; a process for their preparation comprising reacting the 2-(5-dimethylamino-methylfuran-2-ylmethylthio)ethylamine with a functional deri-vative of a benzoic acid of formula
Amidobenzamides having histamine H2 receptors antagonising ac-tion, of formula wherein A is CO or SO2 and B is alkyl, phenyl, pyridyl, pyri-dyl 1-oxyde, pyrazinyl or thienyl; their salts; a process for their preparation comprising reacting the 2-(5-dimethylamino-methylfuran-2-ylmethylthio)ethylamine with a functional deri-vative of a benzoic acid of formula
Description
Amidobenzamides, their salts, process for their preparation-and pharmaceutical compositions containing them.
The present invention relates -to novel amidobenzami-des having a histamine H2 receptor blocking activity, to their salts, to a process for their preparation and to pharmaceutical compositionscontaining them as ac~ive ingredients hfter the subdivision of histamine receptors into H
receptors (Ash and Schild, Brit. J. Pharmac. ChemQther. 1966, 279 427) ancl H receptors ~Black et al., Nature 1972, 236, 335 ) ~ 2 and the discovery that the selective block of the H2 receptors induces an inhibition of the gastric secretion, many products have been proposed as antagonists of the histamine H2 receptors, hereinafter referred to as "H2blockers". Thus, the compounds having received the International Non-proprietary Names burimami-de, metiamide, cimetidine, ranitidine, tiotidine, etintidine, ox-metidine have formed the subject matter of a large number of sci-entific publications and one of them, cimetidine, already consti-tutes a tool in the doctor's hand for the treatment of the ulcer-ous disease.
All of the above-mentioned products are characterised by the presence in their molecule of the following structure:
-NH-C NH-Y
wherein Y represents an oxygen or sulfur atom or an N-CN or CH-N02 group, said structure being linear or included in a cycle as in the case of oxmetidine. The above mentioned products are therefore all characterised by the presence of two geminal nitrogen atoms on a carbon atom.
The French Patent Application No 2 471 376 describes and claims benzamides of formula Rl R2 ~/ I I
/ X \
RCH2 CH2SCH2C~12NI I -CO- R3 wherein R is the dimethylamino or l-pyrrolidinyl group; Rl and R2 are each hydrogen or an alkyl group of from 1 to 3 carbon atoms; R3 is hydrogen, an alkyl group of from 1 to 3 carbon atoms (optionally substituted by a member selected from the group consisting of cyano, alkoxy of from 1 to 3 carbon atoms, phenyl and pentagonal or hexagonal heterocyclic groups~, a cy-cloalkyl group of from 3 to 6 carbon atoms, an alkenyl group of from 2 to 5 carbon atoms (optionally substituted by a member se-` lected from the group consisting of alkoxy of from 1 to 3 carbon atoms, phenyl and phenoxy groups), an aryl group of from 6 to 10 carbon atoms (optionally substituted by one or two members selec-ted from the group consisting of hydroxy, halogen, nitro, sulfa-moyl, alkyl of from 1 to 3 carbon atoms, alkoxy of from 1 to 3 carbon atoms, alkanoyl of from 1 to 3 carbon atoms; alkoxycarbo-nyl of from 2 to 4 carbon atoms, dialkylamino of from 2 to 4 car-bon atoms and alkanesulfonyl oF from 1 to 3 carbon atoms~, or a pentagonal or hexagonal heterocyclic group (eventually substitu-ted by a member selected from the group consisting of oxo, halo-gen, alkyl of from l to 3 carbon atoms and alkoxy of from 1 to 3 carbon atoms) and X is oxygen or sulfur, as well as their phar.na-ceutically acceptable acid addition salts.
Among the compounds described in the above-mentioned patent, the compound of formula II where R = dimethylamino, Rl =
R2 = H, and R3= 4-sulfamoylphenyl, namely the N-L2-(5-dimethylami-- nomethylfuran-2-ylmethylthio-)ethyl~-4-sulfamoylbenzamide,as oxalate, shows anED50 of 2.54 mg/kg in the gastric acid secretion inhibit-ing activity in the rat.
The above French patent application, which provides compounds not having the structure I, in its general formula doesn't include any amidobenzamide , namely any benzamide sub-stituted in the benzene ring by an acylamido or sulfonylamido group.
It is also known that histamine H2 receptors are lo-cated not only in the gastric mucous membrane but also in the sinusal node, in the ventricular myocardium and in the coronary vessels and that the known H2 blockers are active both cn the cardiac and gastric receptors. Thus, the block of the cardiac H2 receptors may be the cause of the bradycardia and oF the asystolia obserYed as side effects in the treatment of the ul-cerous disease by cimetidine tClinica Terapeutica, 1981, 9~, 81-91, in part:icular page 84).
It is therefore desiderable to have available com-pounds which present a dissociation between the gastric and cardiac H2 receptor blocking activities, in favour of the former, which are further capable of giving lower side effects at cardiac level.
I-t has now been found that certain novel amidobenza-mides, not hav;ng the structure I hereinabove, have a good action antagonising the histamine H2 receptors and that this action is preferably directed towards the gastric receptors.
It has also surprisingly been found that the H2block-ing action occurs at a satisfactory level onlv when the "amido"
group is in the meta position of the benzamide phenyl ring.
It has also been found that said novel amidobenzamides don't present the charac~eristical side effects of the compounds with H2 blocking activity, particularly cimetidine5 such as the anti-andromyogenic effect.
Thus, according to one of its aspects, the present invention is to provide novel amidobenz-amides of formula:
~CO-NH ~CH2CH2-5-CH~CH2N ~ I ~ I
NH-A-~
.
wherein A represents a CO or SO2 group and B represents an alkyl group of from l to 6 carbon atoms or a phenyl, lQ pyridyl, pyridyl l-oxide, pyrazinyl or thienyl group, as well as their pharmaceutically acceptable salts. These novel products are formed by the process described below or by an obvious chemical equivalent thereof.
The pharmaceutically acceptable salts lnclude the non-toxic salts derived from mineral or organic acids salifying one or the two basic functions present in the molecule of the compounds of formula III, such as hydrochloride, hydrobromide, sulfate, succinate, tartrate, citrate, fumarate, maleate, 4,4'-methylene-bis-(3-hydroxy 2-naphthoate), hereinafter referred to as "pamoate", 2-naphthalene-sulfonate, hereinafter referred to as "napsylate", methanesulfonate, hereinafter referred to as "mesylate", p-toluenesulfonate, herein-after referred to as "tosylate", and the like.
25According to another of its aspects, the present invention relates to a process for the preparation of compounds of formula III above, said process comprising treating tne 2-(5-dimethylaminomethylfuran-2-ylmethyl-thio)ethylamine of formula:
H2N-CH2CH2S-CH ~ 2 \ H iV
,, ; .~, "
-4a-with a functional derivative of the benzoic acid of formula:
~ ~ COOH
~=
NH-A-B
. .
lQ
/
-- _ whereirl A and B are as hereinabove defined, in an organic solvent at a temperature between 0C and the boiliny tempe rature of the solvent employed. The compound thus obtained may be converted into its pharmaceutically acceptable salts.
S The anhydride,amixed anhydride, thechloride oran active ester may beusedas a suitable functional derivative.
A preferred functional derivative of the acid of formula V above i$ represented by the following forrnula ~ COOR VI
NH~A-B
wherein A and B areashereinbefore defined and R represents a r,itro-phenyl, methoxyphenyl, trityl or benzhydryl group.
lS The reaction temperature may vary between OC and the boiling point of the solvent employed,but-the operationisgenerally carried ou-t at room temperature or at 3C-50C. It may be preferable to carry out the reaction in the cold when it is exothermic, as in the caseof thechloride beingused as a functional derivat1ve of the benzoic acid of ~ormula V.
An alcohol~such as methanol orethanol,orahalo~enated sol-vent, such as methylene chloride, dichloroethane~ chloroFornl and the like, is preferably used as a reaction solvent, but other organic so`lvents cornpatible with the reagents employed, for example dioxan, tetrahydrofuran or a hydrocarbon such as hexane may also be used.
The reaction may be carried out in the presence of a pro-ton acceptor, for example an alkaline carbonate or a tertiary amine, when hydrochloric acid, or another acid, forms during the reaction, but this proton acceptor is not indispensable for ob-taining the final product.
The reaction is fairly rapid; after 2-4 hours at room temperature or at 30-50C the reaction is generally over and the amidobenzamide of formllla III obtained is isolated according to conventional techniques in the form of free base orofone of its salts.
The free base may be converted into one of its 5 pharmaceutically acceptable salts by treatment with a solution of the suitable acid in an organic solvent. Iftheamidobenzamide IIIis isolated asa salt,the corresponding free base can be split-tedo~f ~ith an alcaline hydroxide or carbonate.
The novel compounds of formula III of the present in-lû vention, 3s well às their pharmaceutically acceptable salts, actas selective antagonists of the histamine H2 receptors by selecti-vely inhibiting the gastric secretion at gastric H2 receptor le-vel with slight activity on the cardiac H2 receptors andare there-fore useful for the treatment of the ulcerous disease.
The selective activity of the products of the present invention towards the receptors of type H2 is confirmed by the absence of activity of type ~ in the test of the contraction induced by histamine on the isolated guinea pig ileum.
The antagonistic activity of the amidobenzamides of the 2û present invention towards the gastric histamine H2 receptors was confirmed in the test of the antisecretory activity based on the antagonism for the hypersecretion induce~ by histamine in rat according to the method of Ghosh and Schild (Brit. J. Pharmacol.
195~, 13, 5~). According to this test, a gastric acid hypersecretion is induced by intravenous infusion of a sub-maximal dose of histami ne equivalent to 15 mcmol/kg/hour and the gastric secretion is mea-sured by perfusion of a physiological solution at a constant speed in the stomach of the animal.
Table I shows, for the representative compounds of the present invention, indicated b~ their codenumbers,and for three re-ference compounds, namely 2-cyano-1-methyl-3-r~L¦5-methylimidazol-4-yl)methylthio7ethyl7guanidine, hereinafter designated by its International Non-proprietary Name,"cimetidine", N L~ di-methylanlino)nlethyl7furTuryl7thi~7ethyl~ methyl-2-nitro-1,1-ethenediamine, hereinafter designated by its International Non-proprietary Name "ranitidine" and N-L2-~5-dimethylaminomethyl-furan-2-ylmethylthio)ethy3-4-sulfamoyl benzamide; described in the above-mentioned Patent Application FR 2 471 37-6, hereinafter~
designated "Compound A", the dose (in mcmol/kg by intraYenous route in a single administra~ion) which inhibits by 50C~ the gastric hypersecretiQn induced by histamine (ID50). Such a:1D50 lt) represents the index of the gastric ~ blocking action.
` TABLE I
~ . . . ~
I3sO Relative potency Compound (mcmol/kg) (cimetidine - 1) . . . _ __ __ ___ __ Cimetidine 0.95 1.00 Ranitidine 0.25 3.80 Compcund A 2.26 0.42 - CM 57822 0.98 0.97 t CM 57888 0.63 1.50 2C SR 57912 0.33 2,88 SR 57922 1.15 0.82 SR 57927 A 1~15 Oo82 SR 57933 1.82 0.52 SR 57975 0.93 1.02 SR 57981 A 0.49 1.94 . _ __ . _ .. .... _ . ~
It results form this table that all the representative compounds of the present invention are more active than Compound A
and that most of them have an activity comparable with or superior to that of cimetidine.
~. ..
lwo products, namely SR 57981A andSR 57912 are very powerful and the activity of the latter is very close to that of ranitidine.
The antagonistic activity of the compounds of the present invention towards the cardiac histalmine H2 receptors has been assessed in the test of the inhibition of the increase in the frequency inducecl by histamine on the right atrium of the guinea pig (~. Reinhardt et al., Agents and Actions 1974, 4;
217-221).
Table II shows, for four representative compounds of the present invention, clesignated by their code numbers CM 57822, CM 57888, SR 57912 and SR 57922 as well as for cimetidine, rani-tidine and Compound A, the concentration of product under examina-tion which inhibits by 50Cb the increase in the frequency induced by histamine on the isolated right atrium of the guinea pig (IC50).
Such an IC50 represents the index of cardiac H2 blocking action.
TABLE II
. ~ . . ~,_ .
Compound IC50 Relative potency mcmol/kg l (cimetidine = 1) __ .... .... ~ . .. _.. ~
Cimetidine 4 10~7 Ranitidine 8-10-8 S
Compound A 3.1-iO-7 1.3 CM 57822 2 1 o-6 0.2 CM 57888 5.9 10~7 0.67 SR 57912 5 10-6 0.08 SR 57922 6-1 o-6 0.06 . . . __ ~ _ . .. _ _ . _ ~t results from this table that all the representative compounds of the present invention are less active than cimetidine as cardiac H2 blocking agents, whils-t Compound A is more active.
Thus, the compounds of the present invention, in com~
parison with the products of the prior art, show a good disso-ciation between cardiac and gastric H2 blocking activities in favour o-F the latter.
The anti-andromyogenic effect of a representative compound of the present invention, namely CM 57888, has been assessed in comparison with cimetidine and ranitidine in immatu-re Sprague Dawley rats ~9 each lot) of CD (SD) BR (Charles River -France)strain, castrated at the age of 22-23 days and whose geni-tals as well as the levator ani muscle have been stimulated by a daily injection of testosterone.
Testosterone was administered by sub~cutaneous route, suspended in a vehic1e for steroids, both at the dose of 0.2 mg/
animal/daY~and 0.4 mg/animal~day. For each dose of testosterone, cimetidine, ranitidine and CM 57888 were simultaneously in~ected by intraperitoneal route, in saline, in the case of ranitidine and suspended in a vehicle for steroids for the two other substances;
the administered doses were 400 mg/kg/day for cimetidine, 100 m~t kg/day for ranitidine and 200 mg/kg/day for CM 57888. ~s a control it was used a lot of animals treated with the vehicles only. The treatment lasted 8 days. The animals were killed 24 hours after the last injection, the ventral prostate, the seminal vescicles and the levator ani were immediately drawn and weighed.
It has been found that the three substances sho~ an anti-androgenic and anti-anabolising activity. However, at the employed doses, the activity of CM 57888 was much lower than that of the reference compounds since, contrary to them, the represen-tative compound of the invention did not exhibit any effect when testosterone was administered at the dose of 0.4 mg/animal/day.
3CI This experiment shows that the compound of the present invention has a reduced possibili-ty of giving the characteristical side ef-fects connected with the anti-andromyogenic acitivity of the known H2 blockers.
With respect to their degree of activity, the com-pounds of the present in~ention are scarcely toxic and present a good therapeutic index.
Thus, according to another of its aspects, the pre-sent invention relates to pharmaceutical compositions contain-ing, as active ingredients, the amidobenzamides of formula III above, as well as their pharmaceutically acceptable addition salts.
~n the pharmaceutical compositions with H2 blocking 13 activity according to the present invention, for oral, sublin-gual, sub-cutaneous, intramuscular, intravenous, transdermic or rectal administration, the active ingredients can be administer-ed in unit forms of administration, with conventional pharmaceu tical carriers, to animals and human beings in the treatment o~
gastric hypersecretion and peptic ulGers.
In order to obtain the desired H2 blocking e~fect, the daily dose of active ingredient may vary between 1 and 100 mg per kg of body weight, preferably from 10 to 50 mg/kg.
ZO Each unit dose may contain from 10 to 1000 rng (pre~
ferably from 100 to 500 mg) of active ingredient in combination with a pharmaceutical carrier. This unit dose may be administered 1 to 4 times daily.
Among the appropriate unit forms of administration, there are tablets, capsules, powders, granules arl oral solutions or suspensions and the forms forsublingual administration, suppo-sitories as well as the forms forparenteral administration.
When a solid composition is prepared in the form of tablets, the ma;n active ingredient is mixed with a pharmaceutical excipient such as gelatine, starch, lactose, magnesium stearate~
talc,arabic gum and the like. The tablets may be coated ~ith sucro-se or other appropriate materials or ~hey may be ~reated so that their activity is extended or delayed and that they continually release a predetermined amount of active ingredient.
A preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture ob-t:ained in soft or hard capsules.
A preparation in the form ~f syrup or elixir may con-tain the active ingredient jointly with a possibly acaloric sweetening agent, methylparaben and propylparaben as antiseptics9 as well as a flavoring agent and an appropriate dye.
~later~dispersible powders or granulates may contain the active inyredient mixed with dispersing agents or wetting agents, or suspending agents such as polyvinylpyrrolidone and the like, and wit:h sweetening or flavoring agents.
For rectal applications, suppositories are prepared with binding agents melting at rectal temperature, for example, cocoa butter or polyethyleneglycols~
For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used, which contain pharmacologically compatible dispersing and/
or wetting agents, for example propyleneglycol or butyleneglycol.
The active ingre(iient may also be formulated in the forrn o~ microcapsules~ possibly with one or more supports or ad-ditives.
The following examples illustrate the invention without, ho~ever, limiting its scope.
E)(AMPLE 1 A mixture of 4.3 g (0.02 mole) of 2-(5-dimethylaminome-thylfuran-2-ylmethylthio)ethylamine and 6 g (0.02 mole) of 4-nitro-phenyl 3-acetamidobenzoate in 150 ml of methanol is stirred at 40~C for 2.5 hours. The solvent is evaporated under reduced pres-sure and the residue is taken up with 100 ml of N hydrochloric acid.
.. . ..
The acid solution is washed twice with 40 ml of ethyl acetate and the pH is adjusted to 7.8 with sodium hydr¢xide. The pro-cluct is thoroughly extracted with ethyl acetate, the organic phase is dried over anhydrous sodium sul~ate and the solvent is evaporated under reduced pressure. The residue is dissol-ved in 20 ml of isopropanol and the solution thus obtained is poured into a solution of 1.7 9 of anhydrous oxalic acid in 20 ml of isopropanol. The precipitate is filtered and crystal-lized from e~hanol. Thus, 6 9 of 3-acetamido-N-L~-(5~dimethyl-aminomethylfuran-2-ylmethylthio)ethy Vbenzamide oxalate, desi~
gnated by its code number CM 57820, are obtained; m.p. 123-126C.
In the same rnanner, by reacting 0.02 mole of 2-(5-di-methylaminomethylfuran-2-ylmethylthio)ethylamine with 0.02 mole of 4-nitrophenyl 3-proprionamidobenzoate, with 0.02 mole of 4-nitrophenyl 3-butyramidobenzoate and, respectively, with 0.02 mole of 4-nitrophenyl 3-trimethylacetamidobenzoate:
the 3-propionamido-N-L~--(5-dimethylaminomethylfuran-2-ylmethyl-thio)ethylJbenzamide oxalate; mOp. 133-135C;
t:he 3-butyramido-N-L~-(5-dimethylaminomethylfuran-2-ylmethylthio)-ethyl7benzamide oxalate; m.p. 125-127C; and, respectively) l:he 3 trimethylacetamido-N-L~-(5-dimethylaminomethylfuran-2-ylme-thylthio)ethy Dbenzamide oxalate; m.p. 153-155C, are obtained.
E:XA~PLE 2 . . _ .
A solution of 0.02 mole of 2-(5-dimethylaminomethylfu-ran-2-ylmethylthio)ethylamine and 0.02 mole of 4-nitrophenyl ~-me-t:hanesulfonamidobenzoate in 150 ml of methanol is heated at 45~C
under stirring for 2 hours. The solvent is evaporated under reduced pressure and the residue is taken up with 100 ml of N hydrochloric acid~ The acid solution is washed with ethyl acetate and the pH is adjusted to 7.5 with sodium hydroxide. The product is thoroughly extracted with ethyl acetate, the organic phase i5 dried over anhydrous sodium sulfate, the solvent is evaporated under reduced ~, , .
pressure and the residue is dissolved in 2Q ml of warm isopro~
panolA The 3-methanesulfonamido-N-L~-(5-dimethylaminomethyl-~uran-2-ylmethyltilio) ethyl7benzamide, designated by its code number CM 57822, is thus obtained. After crystallization from isopropanol, it melts at 109-111C.
~n the same manner, by reacting 0.02 mole of 2-(5 dimethylaminomethylfuran-2-ylmethylthio)ethylamine with 0.02 rnole of 4-nitrophenyl 3-ethanesulfonamidobenzoate and, respec-tively~ with 0.02 mole of 4-nitrophenyl 3-butanesulfonamido-benzoate,there is obtained the 3-ethanesulfonamido-N- L-~-( 5-dimethylaminomethylfuran-2-yl-methylthio)ethyl~benzam;de and, respectively, the 3-butanesulfonamido-N-L~-(5-dimethylaminomethylfuran-2-yl-methylthio)ethyl7benzamide,isolated as oxalate as described in Example 1, SR 57981 A, m.p. 103-110C.
f.XAMPLE 3 To a suspension of 0.05 mole of 3-benzenesulfonamido-benzoic acid and O.OS mole of 4-nitrophenol in 250 ml of anhy-drous methylene chloride, 0.05 mole of dicyclohexylcarbodiimide is added. The mixture is refluxed for 4 hours, then evaporated urlder reduced pressure. The residue is taken up with 300 ml of methanol and to ~he solution thus obtained 0.05 mole of 2-(5-di-methylaminomethylfuran-2-ylmethylthio)ethylamine is added. The reaction mixture is refluxed for 2 hours, then evaporated under reduced pressure to dryness. The residue is thoroughly taken up with 150 ml of ~ hydrochloric acid and 100 ml of ethyl acetate and then filtered off. The organic layer is separated, the aqueous layer is adjusted to pH 7.8 and thoroughly extracted with ethyl acetate. The organic phases are collected, dried over anhydrous sodium sulfate and evaporated under reduce pressure.
The residue is taken up with 40 ml of isopropanol and 9.1 g of 3 benzenesulfonamido-N-L~-(5-dime~hylaminomethylfuran-2-yl-methy1thio)ethyl7benzamide, C~1 57888, are thus obtained; after crystallization from isopropanol the product melts at 119-121C.
In the same manner, 0.05 mole of 3-(3-pyridinesulfo-namido)benzoic acid and, respectively of 3-(2-thiophenesulfona-mido)benzoic acid are reacted with 0.05 mole of 4-nitrophenol in 250 ml of anhydrous methylene chloride in the presence of 0.05 mole ofdicyclohexylcarbodiimide. The active ester thus ob-tained is treated with 0.05 mole of 2-(5-dimethylaminomethylfu-ran-2-ylmethylthio)ethylamine, Thus, the 3-(3-pyridinesulfonarnido)-N-~2-(5-dimethylaminomethylfuran-
The present invention relates -to novel amidobenzami-des having a histamine H2 receptor blocking activity, to their salts, to a process for their preparation and to pharmaceutical compositionscontaining them as ac~ive ingredients hfter the subdivision of histamine receptors into H
receptors (Ash and Schild, Brit. J. Pharmac. ChemQther. 1966, 279 427) ancl H receptors ~Black et al., Nature 1972, 236, 335 ) ~ 2 and the discovery that the selective block of the H2 receptors induces an inhibition of the gastric secretion, many products have been proposed as antagonists of the histamine H2 receptors, hereinafter referred to as "H2blockers". Thus, the compounds having received the International Non-proprietary Names burimami-de, metiamide, cimetidine, ranitidine, tiotidine, etintidine, ox-metidine have formed the subject matter of a large number of sci-entific publications and one of them, cimetidine, already consti-tutes a tool in the doctor's hand for the treatment of the ulcer-ous disease.
All of the above-mentioned products are characterised by the presence in their molecule of the following structure:
-NH-C NH-Y
wherein Y represents an oxygen or sulfur atom or an N-CN or CH-N02 group, said structure being linear or included in a cycle as in the case of oxmetidine. The above mentioned products are therefore all characterised by the presence of two geminal nitrogen atoms on a carbon atom.
The French Patent Application No 2 471 376 describes and claims benzamides of formula Rl R2 ~/ I I
/ X \
RCH2 CH2SCH2C~12NI I -CO- R3 wherein R is the dimethylamino or l-pyrrolidinyl group; Rl and R2 are each hydrogen or an alkyl group of from 1 to 3 carbon atoms; R3 is hydrogen, an alkyl group of from 1 to 3 carbon atoms (optionally substituted by a member selected from the group consisting of cyano, alkoxy of from 1 to 3 carbon atoms, phenyl and pentagonal or hexagonal heterocyclic groups~, a cy-cloalkyl group of from 3 to 6 carbon atoms, an alkenyl group of from 2 to 5 carbon atoms (optionally substituted by a member se-` lected from the group consisting of alkoxy of from 1 to 3 carbon atoms, phenyl and phenoxy groups), an aryl group of from 6 to 10 carbon atoms (optionally substituted by one or two members selec-ted from the group consisting of hydroxy, halogen, nitro, sulfa-moyl, alkyl of from 1 to 3 carbon atoms, alkoxy of from 1 to 3 carbon atoms, alkanoyl of from 1 to 3 carbon atoms; alkoxycarbo-nyl of from 2 to 4 carbon atoms, dialkylamino of from 2 to 4 car-bon atoms and alkanesulfonyl oF from 1 to 3 carbon atoms~, or a pentagonal or hexagonal heterocyclic group (eventually substitu-ted by a member selected from the group consisting of oxo, halo-gen, alkyl of from l to 3 carbon atoms and alkoxy of from 1 to 3 carbon atoms) and X is oxygen or sulfur, as well as their phar.na-ceutically acceptable acid addition salts.
Among the compounds described in the above-mentioned patent, the compound of formula II where R = dimethylamino, Rl =
R2 = H, and R3= 4-sulfamoylphenyl, namely the N-L2-(5-dimethylami-- nomethylfuran-2-ylmethylthio-)ethyl~-4-sulfamoylbenzamide,as oxalate, shows anED50 of 2.54 mg/kg in the gastric acid secretion inhibit-ing activity in the rat.
The above French patent application, which provides compounds not having the structure I, in its general formula doesn't include any amidobenzamide , namely any benzamide sub-stituted in the benzene ring by an acylamido or sulfonylamido group.
It is also known that histamine H2 receptors are lo-cated not only in the gastric mucous membrane but also in the sinusal node, in the ventricular myocardium and in the coronary vessels and that the known H2 blockers are active both cn the cardiac and gastric receptors. Thus, the block of the cardiac H2 receptors may be the cause of the bradycardia and oF the asystolia obserYed as side effects in the treatment of the ul-cerous disease by cimetidine tClinica Terapeutica, 1981, 9~, 81-91, in part:icular page 84).
It is therefore desiderable to have available com-pounds which present a dissociation between the gastric and cardiac H2 receptor blocking activities, in favour of the former, which are further capable of giving lower side effects at cardiac level.
I-t has now been found that certain novel amidobenza-mides, not hav;ng the structure I hereinabove, have a good action antagonising the histamine H2 receptors and that this action is preferably directed towards the gastric receptors.
It has also surprisingly been found that the H2block-ing action occurs at a satisfactory level onlv when the "amido"
group is in the meta position of the benzamide phenyl ring.
It has also been found that said novel amidobenzamides don't present the charac~eristical side effects of the compounds with H2 blocking activity, particularly cimetidine5 such as the anti-andromyogenic effect.
Thus, according to one of its aspects, the present invention is to provide novel amidobenz-amides of formula:
~CO-NH ~CH2CH2-5-CH~CH2N ~ I ~ I
NH-A-~
.
wherein A represents a CO or SO2 group and B represents an alkyl group of from l to 6 carbon atoms or a phenyl, lQ pyridyl, pyridyl l-oxide, pyrazinyl or thienyl group, as well as their pharmaceutically acceptable salts. These novel products are formed by the process described below or by an obvious chemical equivalent thereof.
The pharmaceutically acceptable salts lnclude the non-toxic salts derived from mineral or organic acids salifying one or the two basic functions present in the molecule of the compounds of formula III, such as hydrochloride, hydrobromide, sulfate, succinate, tartrate, citrate, fumarate, maleate, 4,4'-methylene-bis-(3-hydroxy 2-naphthoate), hereinafter referred to as "pamoate", 2-naphthalene-sulfonate, hereinafter referred to as "napsylate", methanesulfonate, hereinafter referred to as "mesylate", p-toluenesulfonate, herein-after referred to as "tosylate", and the like.
25According to another of its aspects, the present invention relates to a process for the preparation of compounds of formula III above, said process comprising treating tne 2-(5-dimethylaminomethylfuran-2-ylmethyl-thio)ethylamine of formula:
H2N-CH2CH2S-CH ~ 2 \ H iV
,, ; .~, "
-4a-with a functional derivative of the benzoic acid of formula:
~ ~ COOH
~=
NH-A-B
. .
lQ
/
-- _ whereirl A and B are as hereinabove defined, in an organic solvent at a temperature between 0C and the boiliny tempe rature of the solvent employed. The compound thus obtained may be converted into its pharmaceutically acceptable salts.
S The anhydride,amixed anhydride, thechloride oran active ester may beusedas a suitable functional derivative.
A preferred functional derivative of the acid of formula V above i$ represented by the following forrnula ~ COOR VI
NH~A-B
wherein A and B areashereinbefore defined and R represents a r,itro-phenyl, methoxyphenyl, trityl or benzhydryl group.
lS The reaction temperature may vary between OC and the boiling point of the solvent employed,but-the operationisgenerally carried ou-t at room temperature or at 3C-50C. It may be preferable to carry out the reaction in the cold when it is exothermic, as in the caseof thechloride beingused as a functional derivat1ve of the benzoic acid of ~ormula V.
An alcohol~such as methanol orethanol,orahalo~enated sol-vent, such as methylene chloride, dichloroethane~ chloroFornl and the like, is preferably used as a reaction solvent, but other organic so`lvents cornpatible with the reagents employed, for example dioxan, tetrahydrofuran or a hydrocarbon such as hexane may also be used.
The reaction may be carried out in the presence of a pro-ton acceptor, for example an alkaline carbonate or a tertiary amine, when hydrochloric acid, or another acid, forms during the reaction, but this proton acceptor is not indispensable for ob-taining the final product.
The reaction is fairly rapid; after 2-4 hours at room temperature or at 30-50C the reaction is generally over and the amidobenzamide of formllla III obtained is isolated according to conventional techniques in the form of free base orofone of its salts.
The free base may be converted into one of its 5 pharmaceutically acceptable salts by treatment with a solution of the suitable acid in an organic solvent. Iftheamidobenzamide IIIis isolated asa salt,the corresponding free base can be split-tedo~f ~ith an alcaline hydroxide or carbonate.
The novel compounds of formula III of the present in-lû vention, 3s well às their pharmaceutically acceptable salts, actas selective antagonists of the histamine H2 receptors by selecti-vely inhibiting the gastric secretion at gastric H2 receptor le-vel with slight activity on the cardiac H2 receptors andare there-fore useful for the treatment of the ulcerous disease.
The selective activity of the products of the present invention towards the receptors of type H2 is confirmed by the absence of activity of type ~ in the test of the contraction induced by histamine on the isolated guinea pig ileum.
The antagonistic activity of the amidobenzamides of the 2û present invention towards the gastric histamine H2 receptors was confirmed in the test of the antisecretory activity based on the antagonism for the hypersecretion induce~ by histamine in rat according to the method of Ghosh and Schild (Brit. J. Pharmacol.
195~, 13, 5~). According to this test, a gastric acid hypersecretion is induced by intravenous infusion of a sub-maximal dose of histami ne equivalent to 15 mcmol/kg/hour and the gastric secretion is mea-sured by perfusion of a physiological solution at a constant speed in the stomach of the animal.
Table I shows, for the representative compounds of the present invention, indicated b~ their codenumbers,and for three re-ference compounds, namely 2-cyano-1-methyl-3-r~L¦5-methylimidazol-4-yl)methylthio7ethyl7guanidine, hereinafter designated by its International Non-proprietary Name,"cimetidine", N L~ di-methylanlino)nlethyl7furTuryl7thi~7ethyl~ methyl-2-nitro-1,1-ethenediamine, hereinafter designated by its International Non-proprietary Name "ranitidine" and N-L2-~5-dimethylaminomethyl-furan-2-ylmethylthio)ethy3-4-sulfamoyl benzamide; described in the above-mentioned Patent Application FR 2 471 37-6, hereinafter~
designated "Compound A", the dose (in mcmol/kg by intraYenous route in a single administra~ion) which inhibits by 50C~ the gastric hypersecretiQn induced by histamine (ID50). Such a:1D50 lt) represents the index of the gastric ~ blocking action.
` TABLE I
~ . . . ~
I3sO Relative potency Compound (mcmol/kg) (cimetidine - 1) . . . _ __ __ ___ __ Cimetidine 0.95 1.00 Ranitidine 0.25 3.80 Compcund A 2.26 0.42 - CM 57822 0.98 0.97 t CM 57888 0.63 1.50 2C SR 57912 0.33 2,88 SR 57922 1.15 0.82 SR 57927 A 1~15 Oo82 SR 57933 1.82 0.52 SR 57975 0.93 1.02 SR 57981 A 0.49 1.94 . _ __ . _ .. .... _ . ~
It results form this table that all the representative compounds of the present invention are more active than Compound A
and that most of them have an activity comparable with or superior to that of cimetidine.
~. ..
lwo products, namely SR 57981A andSR 57912 are very powerful and the activity of the latter is very close to that of ranitidine.
The antagonistic activity of the compounds of the present invention towards the cardiac histalmine H2 receptors has been assessed in the test of the inhibition of the increase in the frequency inducecl by histamine on the right atrium of the guinea pig (~. Reinhardt et al., Agents and Actions 1974, 4;
217-221).
Table II shows, for four representative compounds of the present invention, clesignated by their code numbers CM 57822, CM 57888, SR 57912 and SR 57922 as well as for cimetidine, rani-tidine and Compound A, the concentration of product under examina-tion which inhibits by 50Cb the increase in the frequency induced by histamine on the isolated right atrium of the guinea pig (IC50).
Such an IC50 represents the index of cardiac H2 blocking action.
TABLE II
. ~ . . ~,_ .
Compound IC50 Relative potency mcmol/kg l (cimetidine = 1) __ .... .... ~ . .. _.. ~
Cimetidine 4 10~7 Ranitidine 8-10-8 S
Compound A 3.1-iO-7 1.3 CM 57822 2 1 o-6 0.2 CM 57888 5.9 10~7 0.67 SR 57912 5 10-6 0.08 SR 57922 6-1 o-6 0.06 . . . __ ~ _ . .. _ _ . _ ~t results from this table that all the representative compounds of the present invention are less active than cimetidine as cardiac H2 blocking agents, whils-t Compound A is more active.
Thus, the compounds of the present invention, in com~
parison with the products of the prior art, show a good disso-ciation between cardiac and gastric H2 blocking activities in favour o-F the latter.
The anti-andromyogenic effect of a representative compound of the present invention, namely CM 57888, has been assessed in comparison with cimetidine and ranitidine in immatu-re Sprague Dawley rats ~9 each lot) of CD (SD) BR (Charles River -France)strain, castrated at the age of 22-23 days and whose geni-tals as well as the levator ani muscle have been stimulated by a daily injection of testosterone.
Testosterone was administered by sub~cutaneous route, suspended in a vehic1e for steroids, both at the dose of 0.2 mg/
animal/daY~and 0.4 mg/animal~day. For each dose of testosterone, cimetidine, ranitidine and CM 57888 were simultaneously in~ected by intraperitoneal route, in saline, in the case of ranitidine and suspended in a vehicle for steroids for the two other substances;
the administered doses were 400 mg/kg/day for cimetidine, 100 m~t kg/day for ranitidine and 200 mg/kg/day for CM 57888. ~s a control it was used a lot of animals treated with the vehicles only. The treatment lasted 8 days. The animals were killed 24 hours after the last injection, the ventral prostate, the seminal vescicles and the levator ani were immediately drawn and weighed.
It has been found that the three substances sho~ an anti-androgenic and anti-anabolising activity. However, at the employed doses, the activity of CM 57888 was much lower than that of the reference compounds since, contrary to them, the represen-tative compound of the invention did not exhibit any effect when testosterone was administered at the dose of 0.4 mg/animal/day.
3CI This experiment shows that the compound of the present invention has a reduced possibili-ty of giving the characteristical side ef-fects connected with the anti-andromyogenic acitivity of the known H2 blockers.
With respect to their degree of activity, the com-pounds of the present in~ention are scarcely toxic and present a good therapeutic index.
Thus, according to another of its aspects, the pre-sent invention relates to pharmaceutical compositions contain-ing, as active ingredients, the amidobenzamides of formula III above, as well as their pharmaceutically acceptable addition salts.
~n the pharmaceutical compositions with H2 blocking 13 activity according to the present invention, for oral, sublin-gual, sub-cutaneous, intramuscular, intravenous, transdermic or rectal administration, the active ingredients can be administer-ed in unit forms of administration, with conventional pharmaceu tical carriers, to animals and human beings in the treatment o~
gastric hypersecretion and peptic ulGers.
In order to obtain the desired H2 blocking e~fect, the daily dose of active ingredient may vary between 1 and 100 mg per kg of body weight, preferably from 10 to 50 mg/kg.
ZO Each unit dose may contain from 10 to 1000 rng (pre~
ferably from 100 to 500 mg) of active ingredient in combination with a pharmaceutical carrier. This unit dose may be administered 1 to 4 times daily.
Among the appropriate unit forms of administration, there are tablets, capsules, powders, granules arl oral solutions or suspensions and the forms forsublingual administration, suppo-sitories as well as the forms forparenteral administration.
When a solid composition is prepared in the form of tablets, the ma;n active ingredient is mixed with a pharmaceutical excipient such as gelatine, starch, lactose, magnesium stearate~
talc,arabic gum and the like. The tablets may be coated ~ith sucro-se or other appropriate materials or ~hey may be ~reated so that their activity is extended or delayed and that they continually release a predetermined amount of active ingredient.
A preparation in capsules is obtained by mixing the active ingredient with a diluent and by pouring the mixture ob-t:ained in soft or hard capsules.
A preparation in the form ~f syrup or elixir may con-tain the active ingredient jointly with a possibly acaloric sweetening agent, methylparaben and propylparaben as antiseptics9 as well as a flavoring agent and an appropriate dye.
~later~dispersible powders or granulates may contain the active inyredient mixed with dispersing agents or wetting agents, or suspending agents such as polyvinylpyrrolidone and the like, and wit:h sweetening or flavoring agents.
For rectal applications, suppositories are prepared with binding agents melting at rectal temperature, for example, cocoa butter or polyethyleneglycols~
For parenteral administration, aqueous suspensions, isotonic saline solutions or sterile injectable solutions are used, which contain pharmacologically compatible dispersing and/
or wetting agents, for example propyleneglycol or butyleneglycol.
The active ingre(iient may also be formulated in the forrn o~ microcapsules~ possibly with one or more supports or ad-ditives.
The following examples illustrate the invention without, ho~ever, limiting its scope.
E)(AMPLE 1 A mixture of 4.3 g (0.02 mole) of 2-(5-dimethylaminome-thylfuran-2-ylmethylthio)ethylamine and 6 g (0.02 mole) of 4-nitro-phenyl 3-acetamidobenzoate in 150 ml of methanol is stirred at 40~C for 2.5 hours. The solvent is evaporated under reduced pres-sure and the residue is taken up with 100 ml of N hydrochloric acid.
.. . ..
The acid solution is washed twice with 40 ml of ethyl acetate and the pH is adjusted to 7.8 with sodium hydr¢xide. The pro-cluct is thoroughly extracted with ethyl acetate, the organic phase is dried over anhydrous sodium sul~ate and the solvent is evaporated under reduced pressure. The residue is dissol-ved in 20 ml of isopropanol and the solution thus obtained is poured into a solution of 1.7 9 of anhydrous oxalic acid in 20 ml of isopropanol. The precipitate is filtered and crystal-lized from e~hanol. Thus, 6 9 of 3-acetamido-N-L~-(5~dimethyl-aminomethylfuran-2-ylmethylthio)ethy Vbenzamide oxalate, desi~
gnated by its code number CM 57820, are obtained; m.p. 123-126C.
In the same rnanner, by reacting 0.02 mole of 2-(5-di-methylaminomethylfuran-2-ylmethylthio)ethylamine with 0.02 mole of 4-nitrophenyl 3-proprionamidobenzoate, with 0.02 mole of 4-nitrophenyl 3-butyramidobenzoate and, respectively, with 0.02 mole of 4-nitrophenyl 3-trimethylacetamidobenzoate:
the 3-propionamido-N-L~--(5-dimethylaminomethylfuran-2-ylmethyl-thio)ethylJbenzamide oxalate; mOp. 133-135C;
t:he 3-butyramido-N-L~-(5-dimethylaminomethylfuran-2-ylmethylthio)-ethyl7benzamide oxalate; m.p. 125-127C; and, respectively) l:he 3 trimethylacetamido-N-L~-(5-dimethylaminomethylfuran-2-ylme-thylthio)ethy Dbenzamide oxalate; m.p. 153-155C, are obtained.
E:XA~PLE 2 . . _ .
A solution of 0.02 mole of 2-(5-dimethylaminomethylfu-ran-2-ylmethylthio)ethylamine and 0.02 mole of 4-nitrophenyl ~-me-t:hanesulfonamidobenzoate in 150 ml of methanol is heated at 45~C
under stirring for 2 hours. The solvent is evaporated under reduced pressure and the residue is taken up with 100 ml of N hydrochloric acid~ The acid solution is washed with ethyl acetate and the pH is adjusted to 7.5 with sodium hydroxide. The product is thoroughly extracted with ethyl acetate, the organic phase i5 dried over anhydrous sodium sulfate, the solvent is evaporated under reduced ~, , .
pressure and the residue is dissolved in 2Q ml of warm isopro~
panolA The 3-methanesulfonamido-N-L~-(5-dimethylaminomethyl-~uran-2-ylmethyltilio) ethyl7benzamide, designated by its code number CM 57822, is thus obtained. After crystallization from isopropanol, it melts at 109-111C.
~n the same manner, by reacting 0.02 mole of 2-(5 dimethylaminomethylfuran-2-ylmethylthio)ethylamine with 0.02 rnole of 4-nitrophenyl 3-ethanesulfonamidobenzoate and, respec-tively~ with 0.02 mole of 4-nitrophenyl 3-butanesulfonamido-benzoate,there is obtained the 3-ethanesulfonamido-N- L-~-( 5-dimethylaminomethylfuran-2-yl-methylthio)ethyl~benzam;de and, respectively, the 3-butanesulfonamido-N-L~-(5-dimethylaminomethylfuran-2-yl-methylthio)ethyl7benzamide,isolated as oxalate as described in Example 1, SR 57981 A, m.p. 103-110C.
f.XAMPLE 3 To a suspension of 0.05 mole of 3-benzenesulfonamido-benzoic acid and O.OS mole of 4-nitrophenol in 250 ml of anhy-drous methylene chloride, 0.05 mole of dicyclohexylcarbodiimide is added. The mixture is refluxed for 4 hours, then evaporated urlder reduced pressure. The residue is taken up with 300 ml of methanol and to ~he solution thus obtained 0.05 mole of 2-(5-di-methylaminomethylfuran-2-ylmethylthio)ethylamine is added. The reaction mixture is refluxed for 2 hours, then evaporated under reduced pressure to dryness. The residue is thoroughly taken up with 150 ml of ~ hydrochloric acid and 100 ml of ethyl acetate and then filtered off. The organic layer is separated, the aqueous layer is adjusted to pH 7.8 and thoroughly extracted with ethyl acetate. The organic phases are collected, dried over anhydrous sodium sulfate and evaporated under reduce pressure.
The residue is taken up with 40 ml of isopropanol and 9.1 g of 3 benzenesulfonamido-N-L~-(5-dime~hylaminomethylfuran-2-yl-methy1thio)ethyl7benzamide, C~1 57888, are thus obtained; after crystallization from isopropanol the product melts at 119-121C.
In the same manner, 0.05 mole of 3-(3-pyridinesulfo-namido)benzoic acid and, respectively of 3-(2-thiophenesulfona-mido)benzoic acid are reacted with 0.05 mole of 4-nitrophenol in 250 ml of anhydrous methylene chloride in the presence of 0.05 mole ofdicyclohexylcarbodiimide. The active ester thus ob-tained is treated with 0.05 mole of 2-(5-dimethylaminomethylfu-ran-2-ylmethylthio)ethylamine, Thus, the 3-(3-pyridinesulfonarnido)-N-~2-(5-dimethylaminomethylfuran-
2-ylmethylthio)ethyL7benzamide, SR 57933, in the form of a vitreous solid isolated from diethyl ether, m.p. 80-83C
(dec.) and, respectively, the 3-(2-thiophenesulfonamido)-N-L2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl~benzamide, SR 57975, crystallized from ethyl acetate, m.p. 113-115C, are obtained.
By operating as described in Examples 1-3, by reacting 0.02 mole of Z-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyla-mine with the active ester obtained from 0.02 mole of 3-benzamido-benzoic acid ancl 0.02 mole of 4-nitrophenol in the presence of dicyclohexylcarbodiimide, the 3-benzamido-N-L~-(5-dimethylamino-methylfuran-2-ylmethytlhio)ethyl7benzamide, SR 57916, is obtained.
After crystallization from ethyl acetate3 it melts at 112-115C.
Similarly, by reacting 2-(5-dimethylaminomethylfuran-2-ylmethylthio~ethylamine with, respectively, the active ester of
(dec.) and, respectively, the 3-(2-thiophenesulfonamido)-N-L2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl~benzamide, SR 57975, crystallized from ethyl acetate, m.p. 113-115C, are obtained.
By operating as described in Examples 1-3, by reacting 0.02 mole of Z-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyla-mine with the active ester obtained from 0.02 mole of 3-benzamido-benzoic acid ancl 0.02 mole of 4-nitrophenol in the presence of dicyclohexylcarbodiimide, the 3-benzamido-N-L~-(5-dimethylamino-methylfuran-2-ylmethytlhio)ethyl7benzamide, SR 57916, is obtained.
After crystallization from ethyl acetate3 it melts at 112-115C.
Similarly, by reacting 2-(5-dimethylaminomethylfuran-2-ylmethylthio~ethylamine with, respectively, the active ester of
3-(2-thienylcarboxamido)benzoic acid, 3-(3-pyridinecarboxamido)-benzoic acid, 3-(4-pyridinecarboxamido)benzoic acid, 3-(2-pyridine-carboxamido)benzoic acid and 3-(2-pyrazinecarboxamido)benzoic acid, ...
the 3-(2~thienylcarboxamido)-N-L~-(5-dimethylaminomethylfuran-2-ylmethylthio)e-thy~benzamide, SR 57922, m.p. 116-118C;
the 3-(3-pyridinecarboxamido)-N~L2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethy Vbenzamide dioxalate, SR 57927 A, cry-stallized from 95,~ ethanol, m.p. 137-140C;
the 3-(4-pyridinecarboxamido)-N-L2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl7benzamide dioxalate, SR 57944 A, cry-stallized from 95% ethanol, m.p. 176 178C;
the 3-(2~pyridinecarboxamido)-N-L2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethy~7benzamide oxalate, SR 57953 A, crystal-lized From ethanol, m.p. 143-145C; and the 3-(2-pyrazinecarboxamido)-N L2-(S-dimethylaminomethylFuran-2-ylmethyltilio)ethy Vbenzamide, SR 57939~ m.p. 80-82C, are obtained.
. . .
To asuspension of 9.5 9 (0.037 mole) of 3-~ 3-pyridi-ne l-oxyde)carboxamido7benzoic acid and 5 9 (0.037 mole) of 4-nitrophenol in 400 ml of anhyclrous methylene chloride, 7.7 9 (0.037mole) of dicyclohexylcarbodiimide are added. The mixture is heated at reFlux For 4 hours, then evaporated under reduced pressure. The residue is taken up with 300 rnl of methanol and, to the solution thus obtained, 7.g 9 (0.037 mole) oF 2-~5-dime-thylaminomethylfuran-2-ylmethylthio)ethylamine are added. The reaction mixture is heated at 40C for 2 5 hours and evaporated to dryness under reduced pressure. The residue is thoroughly ta-ken up with 70 ml of water and hydrochloric acid to a strong acidic pH, then the solution is washed with a mixture ethYl acetate :ethanol 9:1. The organic phases are collected, dried over anhydrous sodium sulfate and evaporated under reduced pres-sure to dryness. The residue is l;aken up with 10 ml acetone. Thus,0.3 9 of 3-/~3-pyridine 1-oxyde)carboxamid~7~ L~-(5-dimethylami-nomethylFuran-2-ylmethylthio)ethy~benzamide, designated by its code number SR 57912, are obtained, m.p. 160-162C.
In the same manner, by reactiny 0.037 mole of 2-(5-dimethylanlinomethylfuran-2-ylrllethylthio)ethylamine with the active ester obtained from 0.037 mole o~ 3-l~4-pyridine l-oxyde)carboxamido~ benzoic acid and 0.037 mole of 4-nitrophe-nol in the presence of dicyclohexylcarbodiimide, the 3-Ll4-pyridine l-oxyde)carboxamido7~N-L~-(5-dimethylaminomethylfu-ran-2-ylmethylthio)-ethy~7benzamide, SR 57937~ is obtained which, after crystallization from isopropanol, melts at 145-147C.
. .
To a solution of 1 g of 3-benzenesulfonamido-N-L2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl7benzamide in 15 ml of ethanol, a solution of 0.3 9 of oxalic acid in 10 ml of ethanol is added. The salt which precipitates is filtered, dried and crystallized in 10 ml of 95~O ethanol. Thus, 1 g of 3-benzenesulfonamido-N-L~-(S-dimethylaminomethylfuran-2-ylme-thylthio)ethyl~benzamide oxalate is obtained as a vitreous so-lid.
To a solution of 2g of 3-butanesulfonamido-N~
(5-dimethylaminomethylfuran-2-ylmethylthio)ethy~7benzamide oxa-late in 10 ml of water there is added sodium hydroxide until a strong bas-ic reaction is obtained. The mixture is extracted with a mixture ethyl acetate :ethanol 9 :1, the organic phase is dried over anhydrous sodium sulfate and evaporated to dryness.
Thus, there is obtained 1.5 g of 3-butanesulfonamido-N-L~-~5-dimethylaminomethylfuran-2-ylmethylthio)ethyl7benzamide as an oily yellowish product.
IR : 3.500, 3.000, 1.640 and 1.148 cm~l.
lH N~IR Spectrum. (Solvent: DMSO~d6) ~TMS (ppm): 0.83 (3H, m ~> t), 1.1-I.8 (4H, m), 2.11 (6H, s), 2.63 (2H, m ~ t), 2.9-3.6 (4H, m), 3.34 (2H, s), 3.75 (2H, s) ? 6.15 (2H, m), 6.2-6.8 (4H, m), 8.5 (lH, tb, disappears by addition of D2O).
_____ Tablets comprising one of the pro~ucts described in Examples 1 to 7, having the following composition:
Active substance 100 mg lactose 70 mg pota-to starch 40 mg poIyvinylpyrrolidone 8 mg magnesium stearate 2 mg The mixture of ~he active substance with the lactose and pota-to starch is moistened with a 15% alcohol solution of polyvi-nylpyrrolidone, the granules formed are passed through a 1 mm sieve, mixed with the magnesium stearate and tablets are formed by compression. Weight of a tablet: 220 mg.
The tablets manufactured as described in Example 8 are coated in known manner by a coating for pills consisting essentially of sugar and -talc and the finished pills are polished with beeswax. Weight of a pill: 300 mg.
Capsules comprising one of the products described in Examples 1 5 to 7, having the following composition:
Active substance 200 mg cornstarch 90 mg talc 10 mg The active substance and thé excipients are intimately mixed and 3û the mixture thus obtained is introduced into capsules of gelatine of dimension 1. Contents of a capsule : 30û ms.
3~ 7 .
Suppositories colnprising a product as described in Examples 1 to 7, having the following composition:
Active substance 300 mg mass for suppositories (Witespol W 45) 1.450 mg The finely pulverized active substance is suspended in the mass for suppositories at 37~ and the mixture is poured into moulds which are slightly cooled beforehand. i~eight of a suppository:
1.750 mg.
Tablets comprising one of the products described in Examples 1 to 7, having the following composition:
Active substance 150 mg microcrystalline cellulose75 mg lactose 100 mg magnesium stearate 7 mg talc 13 mg The powders are passed through a 0,3 mm sieve, then the ingre-dients are mixed until a homogeneous mixture is obtained which is compressed and granulated. The granules thus obtained are utili2ed to forrn tablets by compression. Weight of a tablet:
350 mg.
_XAMPLE 13 3y operating as described in Example 12, tablets comprislng one of the products described in Examples 1 to 7~ having the follow-ing composition:
Active substance 350 mg microcrys-talline cellulose100 mg lactose 125 mg magnesium stearate 10 mg talc 15 mg are prepared. Weight of a tablet: 500 mg.
EXAMPLE l4 Tablets comprising one of the products described in Examples l to 7, having the following composition:
Active substance l50 mg microcrystalline cellulose 75 mg talc 15 mg polyvinylpyrrolidone 30 mg precipitated silica 25 mg magnesium s~earate 5 mg All the ingredients, except the lubricant, are intimately mixed in a mixing machine for l5 minutes, then the mixture is binded by gradual addition of water. The mass is passed through a 1.25 mm sieve. The granules are dried in a fluidized bed dryer until a proper wetness is obtained (about 2~o water). To the uniform ~ mass there is added the lubricant and tablets are prepared by compression~ !~eight of a tablet: 300 mg.
In the same manner, tab1ets comprising 250 mg of active substan-ce are prepared.
EXA~IPLE 15 . . .
- Coated tablets comprising one of the products described in Examples l to 7, having the following composition:
Active substance 150 mg carboxyrnethyl starch lO mg microcrystalline cellulose 85 mg lac~ose l35 mg hydrogenated castor-oil lO mg magnesium stearate 5 mg are prepared by operating as described in Example l4. The tablets thus obtained are coated with a film having ~he Following compo-sition:
z7 . 20 buthyl phtalate 0.300 mg dimethylaminoethyl butyl polymethacrylate 1.850 mg polyethyleneglycol 1500 0.080 mg c; precipitated silica 0.020 mg talc 0.900 mg titanium dioxide 1.850 mg dissolved in a solvent which is eliminated by evaporation in a fluidized bed dryer. l~eight of a tablet: 400 mg.
.. . ..
the 3-(2~thienylcarboxamido)-N-L~-(5-dimethylaminomethylfuran-2-ylmethylthio)e-thy~benzamide, SR 57922, m.p. 116-118C;
the 3-(3-pyridinecarboxamido)-N~L2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethy Vbenzamide dioxalate, SR 57927 A, cry-stallized from 95,~ ethanol, m.p. 137-140C;
the 3-(4-pyridinecarboxamido)-N-L2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl7benzamide dioxalate, SR 57944 A, cry-stallized from 95% ethanol, m.p. 176 178C;
the 3-(2~pyridinecarboxamido)-N-L2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethy~7benzamide oxalate, SR 57953 A, crystal-lized From ethanol, m.p. 143-145C; and the 3-(2-pyrazinecarboxamido)-N L2-(S-dimethylaminomethylFuran-2-ylmethyltilio)ethy Vbenzamide, SR 57939~ m.p. 80-82C, are obtained.
. . .
To asuspension of 9.5 9 (0.037 mole) of 3-~ 3-pyridi-ne l-oxyde)carboxamido7benzoic acid and 5 9 (0.037 mole) of 4-nitrophenol in 400 ml of anhyclrous methylene chloride, 7.7 9 (0.037mole) of dicyclohexylcarbodiimide are added. The mixture is heated at reFlux For 4 hours, then evaporated under reduced pressure. The residue is taken up with 300 rnl of methanol and, to the solution thus obtained, 7.g 9 (0.037 mole) oF 2-~5-dime-thylaminomethylfuran-2-ylmethylthio)ethylamine are added. The reaction mixture is heated at 40C for 2 5 hours and evaporated to dryness under reduced pressure. The residue is thoroughly ta-ken up with 70 ml of water and hydrochloric acid to a strong acidic pH, then the solution is washed with a mixture ethYl acetate :ethanol 9:1. The organic phases are collected, dried over anhydrous sodium sulfate and evaporated under reduced pres-sure to dryness. The residue is l;aken up with 10 ml acetone. Thus,0.3 9 of 3-/~3-pyridine 1-oxyde)carboxamid~7~ L~-(5-dimethylami-nomethylFuran-2-ylmethylthio)ethy~benzamide, designated by its code number SR 57912, are obtained, m.p. 160-162C.
In the same manner, by reactiny 0.037 mole of 2-(5-dimethylanlinomethylfuran-2-ylrllethylthio)ethylamine with the active ester obtained from 0.037 mole o~ 3-l~4-pyridine l-oxyde)carboxamido~ benzoic acid and 0.037 mole of 4-nitrophe-nol in the presence of dicyclohexylcarbodiimide, the 3-Ll4-pyridine l-oxyde)carboxamido7~N-L~-(5-dimethylaminomethylfu-ran-2-ylmethylthio)-ethy~7benzamide, SR 57937~ is obtained which, after crystallization from isopropanol, melts at 145-147C.
. .
To a solution of 1 g of 3-benzenesulfonamido-N-L2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl7benzamide in 15 ml of ethanol, a solution of 0.3 9 of oxalic acid in 10 ml of ethanol is added. The salt which precipitates is filtered, dried and crystallized in 10 ml of 95~O ethanol. Thus, 1 g of 3-benzenesulfonamido-N-L~-(S-dimethylaminomethylfuran-2-ylme-thylthio)ethyl~benzamide oxalate is obtained as a vitreous so-lid.
To a solution of 2g of 3-butanesulfonamido-N~
(5-dimethylaminomethylfuran-2-ylmethylthio)ethy~7benzamide oxa-late in 10 ml of water there is added sodium hydroxide until a strong bas-ic reaction is obtained. The mixture is extracted with a mixture ethyl acetate :ethanol 9 :1, the organic phase is dried over anhydrous sodium sulfate and evaporated to dryness.
Thus, there is obtained 1.5 g of 3-butanesulfonamido-N-L~-~5-dimethylaminomethylfuran-2-ylmethylthio)ethyl7benzamide as an oily yellowish product.
IR : 3.500, 3.000, 1.640 and 1.148 cm~l.
lH N~IR Spectrum. (Solvent: DMSO~d6) ~TMS (ppm): 0.83 (3H, m ~> t), 1.1-I.8 (4H, m), 2.11 (6H, s), 2.63 (2H, m ~ t), 2.9-3.6 (4H, m), 3.34 (2H, s), 3.75 (2H, s) ? 6.15 (2H, m), 6.2-6.8 (4H, m), 8.5 (lH, tb, disappears by addition of D2O).
_____ Tablets comprising one of the pro~ucts described in Examples 1 to 7, having the following composition:
Active substance 100 mg lactose 70 mg pota-to starch 40 mg poIyvinylpyrrolidone 8 mg magnesium stearate 2 mg The mixture of ~he active substance with the lactose and pota-to starch is moistened with a 15% alcohol solution of polyvi-nylpyrrolidone, the granules formed are passed through a 1 mm sieve, mixed with the magnesium stearate and tablets are formed by compression. Weight of a tablet: 220 mg.
The tablets manufactured as described in Example 8 are coated in known manner by a coating for pills consisting essentially of sugar and -talc and the finished pills are polished with beeswax. Weight of a pill: 300 mg.
Capsules comprising one of the products described in Examples 1 5 to 7, having the following composition:
Active substance 200 mg cornstarch 90 mg talc 10 mg The active substance and thé excipients are intimately mixed and 3û the mixture thus obtained is introduced into capsules of gelatine of dimension 1. Contents of a capsule : 30û ms.
3~ 7 .
Suppositories colnprising a product as described in Examples 1 to 7, having the following composition:
Active substance 300 mg mass for suppositories (Witespol W 45) 1.450 mg The finely pulverized active substance is suspended in the mass for suppositories at 37~ and the mixture is poured into moulds which are slightly cooled beforehand. i~eight of a suppository:
1.750 mg.
Tablets comprising one of the products described in Examples 1 to 7, having the following composition:
Active substance 150 mg microcrystalline cellulose75 mg lactose 100 mg magnesium stearate 7 mg talc 13 mg The powders are passed through a 0,3 mm sieve, then the ingre-dients are mixed until a homogeneous mixture is obtained which is compressed and granulated. The granules thus obtained are utili2ed to forrn tablets by compression. Weight of a tablet:
350 mg.
_XAMPLE 13 3y operating as described in Example 12, tablets comprislng one of the products described in Examples 1 to 7~ having the follow-ing composition:
Active substance 350 mg microcrys-talline cellulose100 mg lactose 125 mg magnesium stearate 10 mg talc 15 mg are prepared. Weight of a tablet: 500 mg.
EXAMPLE l4 Tablets comprising one of the products described in Examples l to 7, having the following composition:
Active substance l50 mg microcrystalline cellulose 75 mg talc 15 mg polyvinylpyrrolidone 30 mg precipitated silica 25 mg magnesium s~earate 5 mg All the ingredients, except the lubricant, are intimately mixed in a mixing machine for l5 minutes, then the mixture is binded by gradual addition of water. The mass is passed through a 1.25 mm sieve. The granules are dried in a fluidized bed dryer until a proper wetness is obtained (about 2~o water). To the uniform ~ mass there is added the lubricant and tablets are prepared by compression~ !~eight of a tablet: 300 mg.
In the same manner, tab1ets comprising 250 mg of active substan-ce are prepared.
EXA~IPLE 15 . . .
- Coated tablets comprising one of the products described in Examples l to 7, having the following composition:
Active substance 150 mg carboxyrnethyl starch lO mg microcrystalline cellulose 85 mg lac~ose l35 mg hydrogenated castor-oil lO mg magnesium stearate 5 mg are prepared by operating as described in Example l4. The tablets thus obtained are coated with a film having ~he Following compo-sition:
z7 . 20 buthyl phtalate 0.300 mg dimethylaminoethyl butyl polymethacrylate 1.850 mg polyethyleneglycol 1500 0.080 mg c; precipitated silica 0.020 mg talc 0.900 mg titanium dioxide 1.850 mg dissolved in a solvent which is eliminated by evaporation in a fluidized bed dryer. l~eight of a tablet: 400 mg.
.. . ..
Claims (9)
PROPERTY OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS:
1. A process for the preparation of an amidobenzamide of the formula:
wherein A represents a CO or SO2 group and B represents an alkyl group of from 1 to 6 carbon atoms or a phenyl, pyridyl, pyridyl 1-oxide, pyrazinyl or thienyl group, or a pharmaceutically acceptable acid addition salt thereof which comprises reacting the 2-(5-dimethylaminomethyl-furan-2-ylmethylthio)ethylamine of formula:
with a functional derivative of a benzoic acid of formula:
in an organic solvent at a temperature of from 0°C and the boiling temperature of the employed solvent, and optionally converting the compound thus obtained into a pharmaceutically acceptable acid addition salt thereof.
wherein A represents a CO or SO2 group and B represents an alkyl group of from 1 to 6 carbon atoms or a phenyl, pyridyl, pyridyl 1-oxide, pyrazinyl or thienyl group, or a pharmaceutically acceptable acid addition salt thereof which comprises reacting the 2-(5-dimethylaminomethyl-furan-2-ylmethylthio)ethylamine of formula:
with a functional derivative of a benzoic acid of formula:
in an organic solvent at a temperature of from 0°C and the boiling temperature of the employed solvent, and optionally converting the compound thus obtained into a pharmaceutically acceptable acid addition salt thereof.
2. The process of claim 1, wherein the amidobenzamide is isolated in form of a salt thereof and the free base is splitted off from said salt by neutralisation with an alkaline hydroxide or carbonate.
3. The process of claim 1, wherein 2-(5-dimethyl-aminomethylfuran-2-ylmethylthio)ethylamine is reacted with 4-nitrophenyl 3-butanesulfonamidobenzoate to produce 3-butanesulfonamido-N-[2-(5-dimethylamino-methylfuran-2-ylmethylthio)ethyl]benzamide or a pharmaceutically acceptable acid addition salt thereof.
4. The process of claim 1, wherein 2-(5-dimethyl-aminomethylfuran-2-ylmethylthio)ethylamine is reacted with 4-nitrophenyl 3-benzenesulfonamidobenzoate to produce 3-benzenesulfonamido-N-[2-(5-dimethylamino-methylfuran2-ylmethylthio)ethyl]benzamide or a pharmaceutically acceptable acid addition salt thereof.
5. The process of claim 1, wherein 2-(5-dimethyl-aminomethylfuran-2-ylmethylthio)ethylamine is reacted with 4-nitrophenyl 3-(2-thienylcarboxamido)benzoate to produce 3-(2-thiophenecarboxamido)-N-[2-(5-dimethyl-aminomethylfuran-2-ylmethylthio)ethyl]benzamide or a pharmaceutically acceptable acid addition salt thereof.
6. An amidobenzamide of the formula:
wherein A represents a CO or SO2 group and B represents an alkyl group of from 1 to 6 carbon atoms or a phenyl, pyridyl, pyridyl 1-oxide, pyrazinyl or thienyl group, or a pharmaceutically acceptable acid addition salt thereof, whenever produced by the process of claim 1 or by an obvious chemical equivalent thereof.
wherein A represents a CO or SO2 group and B represents an alkyl group of from 1 to 6 carbon atoms or a phenyl, pyridyl, pyridyl 1-oxide, pyrazinyl or thienyl group, or a pharmaceutically acceptable acid addition salt thereof, whenever produced by the process of claim 1 or by an obvious chemical equivalent thereof.
7. 3-butanesulfamido-N-[2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl]benzamide or a pharmaceutically acceptable acid addition salt thereof, whenever produced by the process of claim 3 or by an obvious chemical equivalent thereof.
8. 3-benzenesulfamido-N-[2-(5-dimethylaminomethyl-furan-2-ylmethylthio)ethyl]benzamide or a pharmaceutically acceptable acid addition salt thereof, whenever produced by the process of claim 4 or by an obvious chemical equivalent thereof.
9. 3-(2-thiophenecarboxamido)-N-[2-(5-dimethylamino-methylfuran-2-ylmethylthio)ethyl]benzamide or a pharmaceutically acceptable acid addition salt thereof, whenever produced by the process of claim 5 or by an obvious chemical equivalent thereof.
Applications Claiming Priority (6)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR8113420A FR2509305B1 (en) | 1981-07-08 | 1981-07-08 | BENZAMIDES, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM |
| FR81/13420 | 1981-07-08 | ||
| FR8119967A FR2515181A1 (en) | 1981-10-23 | 1981-10-23 | Amido-benzamide histamine H2 receptor blockers as antiulcer cpds. - selectively block gastric H2 receptors e.g. 3-benzene:sulphamido N-2-5-di:methyl:amino:methyl furan-2-yl-methyl thio:ethyl benzamide |
| FR81/19967 | 1981-10-23 | ||
| FR8123084A FR2518097A1 (en) | 1981-12-10 | 1981-12-10 | Amino-benzamide histamine H2 receptor blockers used for ulcers - are 3-sulphonamido or carboxamido N-2,5-di:methylamino:methyl-2-furyl-methyl-thio:ethyl benzamide derivs. |
| FR81/23084 | 1981-12-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1190927A true CA1190927A (en) | 1985-07-23 |
Family
ID=27251063
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000406813A Expired CA1190927A (en) | 1981-07-08 | 1982-07-07 | Amidobenzamides, their salts, process for their preparation and pharmaceutical compositions containing them |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US4439444A (en) |
| EP (1) | EP0069664B1 (en) |
| AR (1) | AR231288A1 (en) |
| AU (1) | AU547405B2 (en) |
| CA (1) | CA1190927A (en) |
| DD (1) | DD202433A5 (en) |
| DE (1) | DE3262870D1 (en) |
| DK (1) | DK305982A (en) |
| ES (1) | ES513792A0 (en) |
| FI (1) | FI822408L (en) |
| GR (1) | GR76007B (en) |
| HU (1) | HU189599B (en) |
| IL (1) | IL66227A (en) |
| NO (1) | NO822122L (en) |
| NZ (1) | NZ201197A (en) |
| PT (1) | PT75209B (en) |
| YU (1) | YU149482A (en) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2531706A1 (en) * | 1982-08-13 | 1984-02-17 | Sanofi Sa | BENZAMIDES, THEIR SALTS, PROCESS FOR THEIR PREPARATION AND PHARMACEUTICAL COMPOSITIONS COMPRISING THE SAME |
| GB8422461D0 (en) * | 1984-09-05 | 1984-10-10 | Wyeth John & Brother Ltd | Pyridine derivatives |
| US4912101A (en) * | 1987-03-13 | 1990-03-27 | Fujirebio Kabushiki Kaisha | 4-aminomethyl-pyridyl-2-oxy derivatives having anti-ulcer activity |
| GB8921792D0 (en) * | 1989-09-27 | 1989-11-08 | May & Baker Ltd | New compositions of matter |
| WO1994012473A1 (en) * | 1992-11-20 | 1994-06-09 | Kaken Pharmaceutical Co., Ltd. | Acetamide derivative |
| CN102603581B (en) * | 2005-06-22 | 2015-06-24 | 普莱希科公司 | Pyrrolo[2,3-b] pyridine derivatives as protein kinase inhibitors |
| WO2008063888A2 (en) | 2006-11-22 | 2008-05-29 | Plexxikon, Inc. | Compounds modulating c-fms and/or c-kit activity and uses therefor |
| CR20170089A (en) | 2009-04-03 | 2017-07-17 | Plexxikon Inc | PROPANE-ACID COMPOSITIONS-1 - SULFONIC {3- [5- (4-CHLORINE-PHENYL) -1H-PIRROLO [2,3-B] PIRIDINA-3-CARBONIL] -2,4-DIFLUORO-PHENIL} -AMIDA AND THE USE OF THE SAME |
| US8329724B2 (en) | 2009-08-03 | 2012-12-11 | Hoffmann-La Roche Inc. | Process for the manufacture of pharmaceutically active compounds |
| NZ599866A (en) | 2009-11-06 | 2014-09-26 | Plexxikon Inc | Compounds and methods for kinase modulation, and indications therefor |
| MA34948B1 (en) | 2011-02-07 | 2014-03-01 | Plexxikon Inc | COMPOUNDS AND METHODS FOR MODULATING KINASE, AND INDICATIONS THEREOF |
| US9150570B2 (en) | 2012-05-31 | 2015-10-06 | Plexxikon Inc. | Synthesis of heterocyclic compounds |
| WO2022034121A1 (en) | 2020-08-11 | 2022-02-17 | Université De Strasbourg | H2 blockers targeting liver macrophages for the prevention and treatment of liver disease and cancer |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2835695A1 (en) * | 1977-08-29 | 1979-03-15 | Yamanouchi Pharma Co Ltd | NEW HETEROCYCLIC COMPOUNDS, METHODS OF MANUFACTURING AND MEDICINAL PRODUCTS CONTAINING THEM |
| JPS5681578A (en) * | 1979-12-07 | 1981-07-03 | Shionogi & Co Ltd | Novel thioalkyl amide derivative |
-
1982
- 1982-06-23 AU AU85134/82A patent/AU547405B2/en not_active Ceased
- 1982-06-24 NO NO822122A patent/NO822122L/en unknown
- 1982-07-02 GR GR68627A patent/GR76007B/el unknown
- 1982-07-05 EP EP82401252A patent/EP0069664B1/en not_active Expired
- 1982-07-05 DE DE8282401252T patent/DE3262870D1/en not_active Expired
- 1982-07-05 IL IL66227A patent/IL66227A/en unknown
- 1982-07-06 AR AR289895A patent/AR231288A1/en active
- 1982-07-07 DD DD82241472A patent/DD202433A5/en unknown
- 1982-07-07 NZ NZ201197A patent/NZ201197A/en unknown
- 1982-07-07 US US06/396,100 patent/US4439444A/en not_active Expired - Fee Related
- 1982-07-07 HU HU822215A patent/HU189599B/en unknown
- 1982-07-07 ES ES513792A patent/ES513792A0/en active Granted
- 1982-07-07 DK DK305982A patent/DK305982A/en not_active Application Discontinuation
- 1982-07-07 CA CA000406813A patent/CA1190927A/en not_active Expired
- 1982-07-07 PT PT75209A patent/PT75209B/en unknown
- 1982-07-07 FI FI822408A patent/FI822408L/en not_active Application Discontinuation
- 1982-07-08 YU YU01494/82A patent/YU149482A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| AR231288A1 (en) | 1984-10-31 |
| IL66227A0 (en) | 1982-11-30 |
| NZ201197A (en) | 1985-01-31 |
| DE3262870D1 (en) | 1985-05-09 |
| ES8308326A1 (en) | 1983-08-16 |
| DK305982A (en) | 1983-01-09 |
| PT75209A (en) | 1982-08-01 |
| AU547405B2 (en) | 1985-10-17 |
| GR76007B (en) | 1984-08-03 |
| DD202433A5 (en) | 1983-09-14 |
| IL66227A (en) | 1985-07-31 |
| AU8513482A (en) | 1983-01-13 |
| HU189599B (en) | 1986-07-28 |
| YU149482A (en) | 1984-12-31 |
| PT75209B (en) | 1984-06-27 |
| US4439444A (en) | 1984-03-27 |
| NO822122L (en) | 1983-01-10 |
| ES513792A0 (en) | 1983-08-16 |
| FI822408L (en) | 1983-01-09 |
| EP0069664A1 (en) | 1983-01-12 |
| FI822408A0 (en) | 1982-07-07 |
| EP0069664B1 (en) | 1985-04-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA1190927A (en) | Amidobenzamides, their salts, process for their preparation and pharmaceutical compositions containing them | |
| CA1070313A (en) | Derivatives of pyridine | |
| JP2921578B2 (en) | Piperidine compound, its production method and its use | |
| EP0254322A1 (en) | Benzimidazole derivatives | |
| CA1168232A (en) | Isoquinoline derivatives, a process for their preparation, pharmaceutical formulations containing them and their use | |
| US4694008A (en) | Chemical compounds | |
| US4514408A (en) | N-substituted nicotinamide 1-oxide as histamine H2 receptor blockers | |
| US4540699A (en) | N-Substituted pyridinones having histamine H2 -antagonist activity | |
| US4388317A (en) | Pyrimidones having histamine H2 -antagonist activity | |
| US4526995A (en) | 3-Amino-n-[2-(5-dimethylaminomethylfuran-2-ylmethylthio)ethyl]benzamide intermediate | |
| US4576955A (en) | Pyridylalkylenethiopyridyls | |
| US4567176A (en) | 4H-Imidazol-4-ones and their pharmaceutical use | |
| CA1072100A (en) | 3a,4,6,7-tetrahydro-3-phenyl-7-(phenylalkylene) thio-pyrano- (4,3-c) pyrazole-2(3h)-alkanamine and analogs | |
| US5389684A (en) | Naphthalene carboxamides | |
| EP0134096B1 (en) | Aminopyrimidinone derivatives as histamine h2-antagonists | |
| GB1575904A (en) | Phenyl piperazines | |
| CA1271767A (en) | DOPAMINE-.beta.-HYDROXYLASE INHIBITORS | |
| CA1192197A (en) | Thioalkylamide of 1-oxide nicotinic acid, its salts, process for the preparation thereof and pharmaceutical compositions | |
| CA1210392A (en) | Process for preparing n-substituted amides; amides thus obtained | |
| CA1203238A (en) | Process for the preparation of amides | |
| US5171746A (en) | Thiazole and imidazole derivatives and antiulcer composition containing same | |
| US4571398A (en) | Cytosine derivatives having histamine H2 -antagonist activity | |
| US4810811A (en) | Dopamine-beta-hydroxylase inhibitors | |
| US4668801A (en) | 1-(2-carboalkoxy 4-(thienyl-alkyl-amido) phenyoxyl 30 amino 20 propanols, their preparation and applications thereof in therapeutics | |
| CS229935B2 (en) | Production method of 3-amido-n-(2(5dimethylaminomethylfura-2-ylemthylthyltio)benzamide |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MKEX | Expiry |